Risk management and regulations for lower limb medical exoskeletons: a review

Figures & data

Table 1 Safety features related to falling in ReWalk™, Indego™, and Ekso™ exoskeletons

Features	ReWalk	Indego	Ekso
Fall detection and mitigation	None	Detects forward, backward, and sideways falling as it is happening; the device makes adjustments during the course of the fall to position the user for minimal risk of injury	None
Failsafe Feature	In the event of a power failure, the ReWalk collapses slowly	In the event of power failure, knees become locked and hips free	In the event of power failure, knees become locked and hips free
Indications for use	Use only with supervision of a specially trained companion	Use only with supervisions of a specially trained companion	Use in rehabilitation institutions under the supervision of a trained physical therapist

Note: Information is summarized from the de novo or 510(k) documents submitted to the FDA.^27,28,33

Abbreviation: FDA, US Food and Drug Administration.

Table 2 Marketing status of some commercially available devices

Device	The USA	The European Union	Japan
ReWalk™	Approved	Approved
Indego™	Approved	Approved
Ekso™	Approved
HAL™		Approved	Approved
Rex™		Approved

Note: As of November 29, 2016.

Table 3 Inclusion and exclusion criteria in clinical trials

Clinical trial (#index, clinical trial identifier, title)	Device	Inclusion criteria			Exclusion criteria
		Age, years	SCI	Stroke	Muscle	Skin	Cardiology	Bone	Hypertension	ROM	Mentality	Pregnancy
#1 NCT02944669 ReWalk Personal Device Postmarket Study	ReWalk™	≥18	T7-L5	×	Ashworth ≥4		✓	✓	✓	✓	✓	✓
#2 NCT02658656 Exoskeleton Assisted-Walking in Persons With SCI: Impact on Quality of Life	ReWalk	>21	C6-	×	✓	✓		Hip BMD_t <−3.5, Knee BMD <0.60 gm/cm^2	140/90	H >0° K >10°		✓
#3 NCT02322125 Restoring Walking With a Powered Exoskeleton After Spinal Cord Injury	ReWalk	18–70	?	×	✓	✓		BMD_t ≤−3.0	✓			✓
#4 NCT023 14221 Exoskeletal-assisted Walking to Improve Mobility, Bowel Function and Cardio-Metabolic Profiles in Persons With SCI	ReWalk	18–70	Any	×	Ashworth >4	✓	✓	FN or PF BMD_t <−3.5, knee BMD <0.60 gm/cm^2	140/90	✓	MMSE <26	✓
#5 NCT02118194 Home/Work, Community Mobility Skills in the ReWalk Exoskeleton in Persons With SCI	ReWalk	18–65	T1-	×	Ashworth >4	✓	✓	FN or PF BMD_t <−3.5, DF or PT BMD <0.59 gm/cm^2	140/90			✓
#6 NCT02104622 Identify Training Strategies for Progressing Exoskeleton Users Towards Everyday Functional Ambulation	ReWalk	12–85	C6–L5	×		✓	✓	✓	✓	✓	✓	✓
#7 NCT01943669 Exoskeletons for Spinal Cord Injury: A Feasibility Study	ReWalk	18–55	C7–L1	×	Ashworth ≥4			✓	✓	(ROM) H, K <90°		✓
#8 NCT01454570 The ReWalk Exoskeletal Walking System for Persons With Paraplegia	ReWalk	18–65	?	×	Ashworth >4	✓	✓	BMD_t <−3, knee BMD <0.70 gm/cm^2	140/90	H > 35° K >20°		✓
#9 NCT01251549 Safety and Performance Evaluation of ReWalk Reciprocating Gait Orthosis (RGO)	ReWalk	18–55	C7–T12	×	Ashworth ≥4	✓	✓	✓	✓	✓	✓	✓
#10 NCT00627107 A Study Testing Safety and Tolerance of the ReWalk Exoskeleton Suit	ReWalk	18–55	C7–T12	×	✓	✓	✓	✓			✓	✓
#11 NCT02793635 Indego Exoskeleton After SCI	Indego™	18-	Any	×	M. Ash worth ≥4	✓		✓	150/90	✓		✓
#12 NCT02202538 Indego Exoskeleton; Assessing Mobility for Persons With Spinal Cord Injury (SCI).	Indego	18–80	C5-	×	M. Ash worth ≥4	✓		✓	150/90	H,K,A >10°	✓	✓
#13 NCT02545205 New Technology for Individualised, Intensive Training of Gait After Stroke	HAL™	18–70	×	○			✓		✓	✓	✓
#14 NCT02545088 New Technology for Individualised, Intensive Training of Gait After Stroke – Study II	HAL™	18–70	×	○			✓		✓	✓	✓
#15 NCT02410915 A Comparison Between the Exoskeleton Hybrid Assistive Limb and Conventional Gait Training Early After Stroke	HAL™	18–67	×	○			✓		✓	✓	✓
#16 NCT02943915 The WISE Trial – Walking Improvement for SCI With Exoskeleton	Ekso™	18–75	C1–T10	×	M.Ashworth ≥3	✓		✓	✓	H >17° K >12°	✓	✓
#17 NCT02600013 Locomotor Training With Exoskeleton EKSO-GT in Patients With Incomplete Motor Spinal Cord Injury in a Hospital Setting	Ekso	18–70	?	×	M.Ashworth >3	✓	✓	✓	✓	✓	✓	✓
#18 NCT02566850 Investigational Study of the Ekso Bionics Powered Exoskeleton for High-Dosage Use by Individuals With SCI in a Non-Clinical Environment	Ekso	18–65	?	×		✓		✓		H >15° K >10°	✓	✓
#19 NCT02519244 Wearable Lower Extremity Exoskeleton to Promote Walking in Persons With Multiple Sclerosis	Ekso	18–65	?	×	M.Ashworth ≥3	✓	✓	✓	✓	H >15° K >20°	✓
#20 NCT02324322 Non-Ambulatory SCI Walk Using a Robotic Exoskeleton: Effect on Bone and Muscle	Ekso	21–45	C6-T10	×	M.Ashworth ≥3	✓	✓	✓	✓	✓	✓	✓
#21 NCT02314221 Exoskeletal-assisted Walking to Improve Mobility, Bowel Function and Cardio-Metabolic Profiles in Persons With SCI	Ekso	18–70	Any	×	M.Ashworth ≥4		✓	FN or PF BMD_t <−3.5, knee BMD <0.60 gm/cm^2	140/90	H >35° K >20°	MMSE <26	V
#22 NCT02132702 Performance Attributes and User Progression While Using Ekso	Ekso	15–65	C1–L2	×	M. Ash worth ≥4, MMT	✓	✓	✓		H >5° K >5° A >0°		✓
#23 NCT02128152 Mobility Training Using Exoskeletons for Functional Recovery After Stroke	Ekso	18–85	×	○	✓	✓	✓	✓		✓	MMSE > 17	✓
#24 NCT02065830 Safety Study of Outdoor and Indoor Mobility in People With Spinal Cord Injury (ROBOtics Spinal Cord Injury EKSO)	Ekso	18–80	C7–T12	×	M.Ashworth ≥3	✓	✓	✓	✓	✓
#25 NCT01701388 EKSO Trial: Powered Exoskeleton for Ambulation in Subjects With SCI	Ekso	18–65	C7–S1	×	M.Ashworth ≥3	✓		BMD_t <−3		✓	✓
#26 NCT02417532 Safety and Feasibility Evaluation of Robot Assisted Physiotherapy Exercises With REX	Rex™	10–90	C4–L5	×		✓	✓			Various ROMs in hip, knee, and ankle
#27 NCT02790424 Adjustment Exploratory Protocols and Functional Evaluation of New Non Invasive Devices in Patient Volunteers	Rex	≥18	?	?
#28 NCT02790411 Adjustment Exploratory Protocols and Functional Evaluation of New Non Invasive Devices in Healthy Volunteers	Rex	≥18	×	×

Notes: The table was aggregated from ClinicalTrials.gov (https://clinicaltrials.gov/). An additional index that begins with # was added for easier reference in the discussion. In the “Inclusion Criteria”, a cross (×) indicates the type of participants who are excluded; a circle (○) indicates included; a question mark (?) indicates information not available; specifications (eg, “C7–T12”) indicate the specified spinal cord injury level. In the “Exclusion Criteria”, a check mark (✓) indicates that related exclusion criteria exist in this category, although no quantitative measurement was specified. Values in the ROM column are contracture limitations unless indicated otherwise.

Abbreviations: SCI, spinal cord injury; M.Ashworth, modified Ashworth Scale; MMT, manual muscle testing; DF, distal femur; PT, proximal tibia; FN, femoral neck; PF, proximal femur; Rex, robotic exoskeleton; ROM, range of motion; BMD, bone mineral density; BMD_t, t-score of BMD; MMSE, Mini-Mental Status Exam.

Table 4 Published adverse events involving exoskeletons

Type of Accident	Injury	Device	adverse event	Reference
Misalignment	Bone fracture	ReWalk™	Bone fracture at right talus	3007615665-2014-00001 Benson et al^Citation21
Misalignment	Bone fracture	Rex	Bilateral symmetrical bone fracture around shin	3010365481-2016-00001
Device malfunction	Unknown	ReWalk	Device’s left hip stayed at 90° while the right was trying to extend during sit-to-stand	3007615665-2013-00001
Device malfunction	No	Ekso™	Upper left leg structure became separated from the device	3009495988-2015-00002
Device malfunction	No	Ekso	Left foot plate became separated from the rest of the ankle	3009495988-2015-00001
Device malfunction	No	Ekso	Unknown part became separated from the device	3009495988-2015-00004
Device malfunction	No	Ekso	Foot plate became partially separated from the rest of the ankle during use, allowing excessive rotation	3009495988-2015-00003
Device malfunction	No	Ekso	Foot plate had come partially separated from the device during use	3009495988-2015-00005
Device malfunction	No	Ekso	Epoxy bond on the ankle had broken, allowing the ankle to rotate	3009495988-2015-00006
Device malfunction	No	Ekso	Upper left leg structure became separated from the device	3009495988-2015-00007
Skin and tissue damage	Bruising resolved in 4 days	Indego™	User experienced bruising on the torso under one of the tensioning straps before additional padding was placed	Hartigan et al^Citation45
Skin and tissue damage	Bruising resolved in 2 days	Indego	User experienced Grade I skin redness along the lateral upper back for unknown reason	Hartigan et al^Citation45
Skin and tissue damage	Minor	ReWalk	Minor skin abrasions were the most common adverse event encountered (others events unknown)	Yang et al^Citation23
Skin and tissue damage	Minor	Ekso	Two minor incidents involving the device pinching and abrading tissues	Kolakowsky-Hayner et al^Citation10
Skin and tissue damage	Minor	ReWalk	Grade I (n = 5; in three subjects) and II (n = 10; in five subjects) skin damage	Benson et al^Citation21
Skin and tissue damage	Minor	HAL™	Several occurrences of local pain and skin irritation	Nilsson et al^Citation55
Skin and tissue damage	Minor	Ekso	Unknown number of blanchable erythemas of the skin at the thigh and/or shank strap locations	Kozlowski et al^Citation46
Falling	No	Ekso	Multiple falls and loss of balance occurred with a prototype unit. Injury was prevented because of tendering device. Causes include malfunctioning software and accidental power cutoff.	Kolakowsky-Hayner et al^Citation10
Spasticity	No	Ekso	User had moderate ankle clonus, then reduced to mild	Kressler et al^Citation48
Abnormal blood pressure	No	HAL	Orthostatic hypotension (n=4, causing one of them to withdraw)	Ueba et al^Citation54
Use Error	Minor	HAL	Chafed feet due to wrong shoe size	Nilsson et al^Citation55
Unknown	Unknown	ReWalk	Concurrent medical complications (n = 5)	Benson et al^Citation21
Unknown	No	ReWalk	Unknown number of minor skin abrasions, lightheadedness, edema, loss of balance (without falling), and spasticity	Esquenazi et al^Citation40

Notes: The 19-digit numbers (eg, 3007615665-2014-00001) in the Reference column are the Report Number of adverse events reported in MAUDE. The rest in this column are peer-reviewed publications.

Abbreviations: MAUDE, Manufacturer and User Facility Device Experience.

Table 5 Identified risks to health and mitigation measures

Identified risk	Mitigation measure
Instability, falls, and associated injuries	Clinical testing Training software verification, validation, and hazard analysis Wireless EMC and EMI testing Electrical safety testing Design characteristics Nonclinical performance testing and water/particle ingress testing Durability testing Battery testing Labeling
Bruising, skin abrasion, pressure sores, and soft tissue injury	Clinical testing Training Labeling
Diastolic hypertension and changes in blood pressure, and heart rate Adverse tissue reaction Premature battery failure	Clinical testing Training Labeling Biocompatibility assessment Battery testing Labeling
Interference with other electrical equipment/devices	EMC/EMI testing Labeling
Burns and electrical shock	Electrical safety testing Thermal testing Labeling
Device malfunction resulting in unanticipated operation (eg, device stoppage, unintended movement)	Clinical testing Nonclinical performance testing Training Software verification, validation, and hazard analysis Electrical safety testing Battery testing Water/particle ingress testing Wireless testing EMC/EMI testing Flammability testing Labeling
Use error	Clinical testing Training Labeling
Bone fracture (other than caused by falling)a	Training Bone density screening Pressure/torque monitoring Design characteristics Labeling
Long-term secondary effecta	Long-term clinical testing Surveillance program

Notes: Adapted from Table 2 Identified Risks to Health and Mitigation Measures in FDA’s evaluation of ReWalk’s classification. Available from https://www.accessdata.fda.gov/cdrh_docs/pdf13/DEN130034.pdf.²⁷ The entries in this table apply to other lower limb medical exoskeletons that claim being substantially equivalent to ReWalk™.

a The last two rows contain additional risks that are not included in FDA’s original table. Bold entries are addressed in detail in this review.

Abbreviations: EMC, electromagnetic compatibility; EMI, electromagnetic interference; FDA, US Food and Drug Administration.

Figure 1 Entities involved in the risk management of exoskeleton.

Figure 2 Procedures for obtaining medical device approval in the USA, EU, and Japan. The USA requires applications to be approved by a federal agency, namely the FDA, whereas the EU distributes the responsibility to many independent notified bodies. Japan’s government reviews reliability of the manufacturers both on site and via documents, while the USA and the EU leave that responsibility to manufacturers themselves. The bottom panel about Japan was adapted from the diagram on Page 11 in the materials of the 2011 AHC Workshop on Medical Devices. Tamura A. Understanding Japanese medical device requirements. 2011. Available from: https://www.pmda.go.jp/files/000164006.pdf.⁷³

Abbreviations: CE, European Conformity; EU, European Union; FDA, US Food and Drug Administration; MHLW, Ministry of Health, Labour, and Welfare; PMDA, Pharmaceuticals and Medical Device Agency; QMS, quality management system.

Table 6 Standards recommended by the FDA

Category	Standard
Electrical
Software (Entire lifecycle)	IEC 62304 Ed. 1.1 2015–06
EMC/EMI	AAMI/ANSI/IEC 60601-1-2:2014
Electrical safety testinga	IEC 60601-1:2005 (ReWalk™) ANSI/AAMI ES60601-1:2005/(R)20I2 (Indego)
Medical electrical equipment (Home use)	ANSI/AAMI HA60601-1-11:20I5
Mechanical
Durability testing (used in prosthetics)	ISO 10328:2006
Cyclic loading testing (used in prosthetics)	ISO 22675:2006
Particle ingress	ANSI IEC 60529:2004
General
Risk management	ISO 14971:2007
Quality management	ISO 13485:2003
Labeling	ISO 15223-1:20I2
Biocompatibility	ISO 10993-1:2009
Human factors engineering	AAMI ANSI HE75:2009/(R)2013
Training	AAMI TIR49:2013
Application of usability	AAMI ANSI IEC 62366-1:2015
Lithium batteries	UL 1642 5^th ed.

Notes: While the FDA has not recommended any standards specifically applicable to powered exoskeletons, we include current related standards that FDA recommends for Class II medical devices and lower limb prostheses.

a According to the AAMI website, AAMI 60601-1 3^rd ed. is identical to IEC 60601-1 but includes deviations to comply with US National Electric Code (http://www.aami.org/productspublications/ProductDetail.aspx?ItemNumber=1578). These two standards are followed by Indego and ReWalk, respectively.

Abbreviations: AAMI, Association for the Advancement of Medical Instrumentation; ANSI, American National Standards Institute; EMC, electromagnetic compatibility; EMI, electromagnetic interference; FDA, US Food and Drug Administration; IEC, International Electrotechnical Commission; ISO, International Organization for Standardization.

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